Achiral additives dramatically enhance enantioselectivities in the BINOL-Ti(IV) complex catalyzed aldol condensations of aldehydes with Chan's diene

Article abstract of DOI:10.1016/j.tetasy.2010.01.008

Achiral additives can dramatically enhance the enantioselectivities in the BINOL-Ti(IV) complex catalyzed aldol condensations of aldehydes with Chan's diene. The best results were obtained by using 2.0 equiv of LiCl with respect to (S)-BINOL/Ti(Oi-Pr)

Full text of DOI:10.1016/j.tetasy.2010.01.008

Tetrahedron: Asymmetry 21 (2010) 156–158
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Achiral additives dramatically enhance enantioselectivities in the BINOL–Ti(IV)
complex catalyzed aldol condensations of aldehydes with Chan’s diene
a,
Qinyao Xu a, Jianghui Yu a, Fengyan Han a, Juan Hu a, Weiping Chen b, , Liping Yang
*
*
a Department of Chemistry, East China Normal University, Shanghai 200062, China
b Solvias AG, WRO-1055.6.68B, Mattenstrasse 22, Postfach, CH-4002 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 December 2009
Accepted 7 January 2010
Achiral additives can dramatically enhance the enantioselectivities in the BINOL–Ti(IV) complex cata-
lyzed aldol condensations of aldehydes with Chan’s diene. The best results were obtained by using
2.0 equiv of LiCl with respect to (S)-BINOL/Ti(Oi-Pr)4 as the additive. In the presence of 4.0 mol % of LiCl
and 2.0 mol % of BINOL/Ti(Oi-Pr)4, all aldehydes tested gave d-hydroxy-b-ketoesters as almost pure single
enantiomers. Moreover, the present catalyst system was highly effective on reducing the catalyst load-
ings to 0.1 mol %.
Published by Elsevier Ltd.
1. Introduction
R1
O
R2
O
1) RCHO
chiral catalyst
Me3SiO
OSiMe3
OMe
Asymmetric catalysis that provides enantiomerically enriched
products is of central importance to modern synthetic and phar-
maceutical chemistry; a great number of catalytic asymmetric
transformations have been developed over the last decade.1
Although most often enantioselectivities of 90–95% ee. have been
achieved for a variety of transformations in the research labora-
tory, this is usually not sufficient for industrial needs, particularly
when it comes to pharmaceutical intermediates and products.
Moreover, the catalyst productivity, catalyst activity, catalyst sta-
bility, and mild reaction conditions are very important for large-
scale practical applications. Chiral Lewis acid-catalyzed enantiose-
lective aldol reactions of aldehydes with O-silyldienolates 1 and 2
(Chan’s diene) represent some of the most efficient, chemoselec-
tive and straightforward methods for the synthesis of enantiome-
rically enriched d-hydroxy-b-ketoesters (Scheme 1), versatile
intermediates for the synthesis of complex, biologically active
compounds, and natural products.2,3
Recently, Scettri et al. reported the aldol condensations of alde-
hydes with Chan’s diene 2 catalyzed by a BINOL–Ti(IV) complex.4
In the presence of molecular sieves and 2–8 mol % of (R)-BINOL/
Ti(Oi-Pr)4, the reaction of an aldehyde with Chan’s diene 2 for 2 h
at À78 °C, then 16 h at room temperature gave product 3 in 48–
94% yield and 83–99% ee for aromatic aldehydes, and 31–70% yield
and 87–98% ee for aliphatic aldehydes, after desilylation. Over the
course of developing a new practical route to anti-obesity agent
or
OSiMe3
2) desilylation
1
2
OH
O
O
R
OMe
3
Scheme 1.
inhibitor,5 we found that the reaction of the requisite aldehyde
with Chan’s diene catalyzed by BINOL–Ti(IV) complex gave very
low enantioselectivity in the absence of molecular sieves, but that
the enantioselectivities could be dramatically improved upon
when a Chan’s diene contaminated with lithium chloride was used.
Considering the effect of additives on asymmetric catalytic reac-
tions6 and the use of lithium chloride in the asymmetric nitroaldol
reaction7a and conjugate addition,7b we decided to investigate
their influence on this transformation.
BINOL–Ti(IV) is one of the most popular chiral Lewis acid cata-
lysts.8 The effect of achiral additives on asymmetric reactions cat-
alyzed by BINOL–Ti(IV) has been documented previously. For
example, molecular sieves have been added to most reactions,8 hy-
drated molecular sieves added for ene9a and Diels–Alder reac-
tions,9b phenols for aldols,9c,d alkynylations of aldehydes9e and
allylations of aldehydes;9f water for ene reactions,9g ring-opening
reactions,9h and sulfoxidations;9i,j and finally, triphenylphosphine
for ring-opening reactions.9k
* Corresponding authors. Tel.: +86 (021) 62232487; fax: +86 (021) 62232487
(L.Y.).
E-mail address: lpyang@chem.ecnu.edu.cn (L. Yang).
0957-4166/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2010.01.008

Q. Xu et al. / Tetrahedron: Asymmetry 21 (2010) 156–158
157
Table 2
2. Results and discussion
Asymmetric aldol condensations of Chan’s diene with different aldehydes catalyzed
by BINOL/Ti(Oi-Pr)4 in the presence of lithium chloridea
Initially in this study, the effect of various achiral additives on
the aldol reaction of cinnamaldehyde with Chan’s diene 2 was
examined. Thus, in the presence of (S)-BINOL/Ti(Oi-Pr)4(0.1 mmol)
and an achiral additive in the desired amount, cinnamaldehyde 4a
(5 mmol) was reacted with Chan’s diene (10 mmol) in THF at room
temperature, followed by desilylation, to give the product (S)-3a
(Table 1). In the absence of additives, the reaction gave very low
enantioselectivity (4% ee, entry 1). Many achiral additives, of differ-
ent properties, could significantly enhance the enantioselectivity.
The most outstanding results were achieved using LiCl as the addi-
tive (entry 18–20), giving products in up to 97% ee. Best results
were obtained using 2.0 equiv of LiCl with respect to (S)-BINOL/
Ti(Oi-Pr)4 (entry 19). However, only a marginal effect on the
enantioselectivity was observed on reducing LiCl to 1.0 equiv or
increasing it to 4.0 equiv (entries 18 and 20).
1) (S)-BINOL/Ti(Oi-Pr)4 (2 mol%)
Me3SiO
OSiMe3
OMe
LiCl (4 mol%), THF, rt, 12 h
+
RCHO
2) PPTS, MeOH, rt, 2 h
4
2
OH
O
O
R
OMe
3
Entry
R
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
C6H5CH@CH–
C6H5–
4-CH3O–C6H4–
4-NO2–C6H4–
3-NO2–C6H4–
n-C2H5–
3a
3b
3c
3d
3e
3f
95
93
90
75
75
45
55
97
99
99
95
99
96
99
n-C11H23
–
3g
Table 1
Asymmetric aldol condensation of cinnamaldehyde with Chan’s diene catalyzed by
a
Reaction conditions: (1) cinnamaldehyde (5.0 mmol), (S)-BINOL (0.1 mmol),
Ti(Oi-Pr)4(0.1 mmol), LiCl (0.2 mmol), Chan’s diene (10.0 mmol),THF (16 mL), room
temperature, 12 h; (2) PPTS (1 mmol), MeOH (10 mL), room temperature, 2 h.
BINOL/Ti(Oi-Pr)4in the presence of achiral additivesa
1) (S)-BINOL/Ti(Oi-Pr)4 (2 mol%)
b
Me3SiO
OSiMe3
OMe
All the yields refer to isolated, chromatographically pure compounds.
Determined by HPLC with AD-H column.
achiral additive, THF, rt,
c
CHO
+
Ph
2) PPTS, MeOH, rt, 2 h
4a
2
namaldehyde with Chan’s diene 2 was examined. As shown in
Table 3, the reaction with reduced catalyst loadings as low as
0.1 mol % was highly effective, affording the product in 79% yield
and with 95% ee. The reaction using 0.05% catalyst was still effec-
tive (entry 5) but further reduction of catalyst loadings gave signif-
icantly lower enantioselectivities (entry 6–7).
OH
O
O
Ph
OMe
3a
Entry Additive Equivalent (based on
cat.)
Time
(h)
Yieldb
(%)
eec (%)
1
2
2
90
89
91
90
80
90
93
93
85
88
75
92
93
75
90
90
90
92
95
91
4
6
2
3
Water
4 Å MS
4 Å MS
EtOH
Pyridine
Et3N
i-PrNH2
TMEDA
PhOH
PhCO2H
AcOH
ZnCl2
MgCl2
LiBr
2.0
Table 3
12
12
30
12
12
12
30
12
54
12
12
54
12
12
12
12
12
12
23
89
73
29
74
52
92
56
69
36
12
85
73
38
28
95
97
95
Asymmetric aldol condensation of cinnamaldehyde with Chan’s diene catalyzed by
4d
5
a
BINOL/Ti(Oi-Pr)4
2.0
2.0
2.0
2.0
1.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
2.0
4.0
6
7
8
9
1) (S)-BINOL/Ti(Oi-Pr)4
Me3SiO
OSiMe3
OMe
LiCl , THF, rt
CHO
+
Ph
2) PPTS, MeOH, rt, 2 h
10
11
12
13
14
15
16
17
18
19
20
4a
2
OH
O
O
Ph
OMe
3a
KCl
NaCl
LiCl
LiCl
Entry
Catalyst (mol %)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
2.0
1.0
0.5
0.1
0.05
0.01
0.005
12
12
24
60
84
95
95
89
79
70
40
30
97
96
96
95
88
35
12
LiCl
a
Reaction conditions: (1) cinnamaldehyde (5.0 mmol), (S)-BINOL (0.1 mmol),
Ti(Oi-Pr)4 (0.1 mmol), additives in the specified amount, Chan’s diene (10.0 mmol),
THF (16 mL), room temperature, 12 h; (2) PPTS (1 mmol), MeOH (10 mL), room
temperature, 2 h.
108
108
b
All the yields refer to isolated, chromatographically pure compounds.
Determined by HPLC with an AD-H column.
The reaction was performed according to Scettri’s procedure at À78 °C.
c
a
Reaction conditions: (1) cinnamaldehyde (5 mmol), (S)-BINOL and Ti(Oi-Pr)4 in
the desired amount, LiCl (2 equiv to catalyst), Chan’s diene (10.0 mmol), THF
(16 mL), room temperature; (2) PPTS (1 mmol), MeOH (10 mL), room temperature,
2 h.
d
Next, the scope of aforementioned reaction was extended by
using a number of aromatic and aliphatic aldehydes in the pres-
ence of 2.0 equiv of LiCl with respect to (S)-BINOL/Ti(Oi-Pr)4(Ta-
ble 2). It was found that the novel system was highly efficient for
the reactions of a variety of aldehydes, including aromatic, olefinic,
and aliphatic derivatives. In all cases, full conversion of the alde-
hydes was obtained within 12 h at room temperature, giving prod-
ucts with almost perfect enantioselectivities.
b
Isolated yield.
Determined by HPLC with an AD-H column.
c
3. Conclusion
In conclusion, achiral additives can dramatically enhance the
enantioselectivities in the BINOL–Ti(IV) complex-catalyzed aldol
condensations of aldehydes with Chan’s diene. The best results
were obtained by using 2.0 equiv of LiCl with respect to (S)-BI-
To further evaluate the catalytic efficiency of the present sys-
tem, the effect of the catalyst loading on the aldol reaction of cin-

158
Q. Xu et al. / Tetrahedron: Asymmetry 21 (2010) 156–158
2828. and references cited therein; Aldol condensation of optically active b-
hydroxy esters: (b) Nakamura, R.; Tanino, K.; Miyashita, M. Org. Lett. 2005, 7,
2929–2932. and references cited therein; Reduction of 4,5-epoxy-3-oxo-esters:
(c) Tosaki, S.; Nemoto, T.; Ohshima, T.; Shibasaki, M. Org. Lett. 2003, 5, 495–
498; Addition of organometallic reagents to oxiranyl-3-oxo-butyric acid ester:
(d) Dakin, L. A.; Panek, J. S. Org. Lett. 2003, 5, 3995–3998; Blaiser reaction of
optically active b-hydroxy nitriles: (e) Wang, F.-D.; Yue, J.-M. Eur. J. Org. Chem.
2005, 2575–2579. and references cited therein; Carbonylation of optically
active epoxides followed by aldol condensation: (f) Goodman, S. N.; Jacobsen, E.
N. Angew. Chem., Int. Ed. 2002, 41, 4703–4705.
NOL/Ti(Oi-Pr)4 as the additive. In the presence of 4.0 mol % of LiCl
and 2.0 mol % of BINOL/Ti(Oi-Pr)4, all the aldehydes tested gave d-
hydroxy-b-ketoesters as almost pure single enantiomers . More-
over, the present catalyst system was highly effective in reducing
the catalyst loadings to 0.1 mol %. This new methodology has been
successfully used in the practical synthesis of the anti-obesity
agent Orlistat.10 Mechanistic studies and the application of the
present catalyst system in other reactions are currently in progress.
4. (a) Soriente, A.; De Rosa, M.; Villano, R.; Scettri, A. Tetrahedron: Asymmetry
2000, 11, 2255–2258; (b) Soriente, A.; De Rosa, M.; Stanzione, M.; Villano, R.;
Scettri, A. Tetrahedron: Asymmetry 2001, 12, 959–963; (c) Villano, R.; Acocella,
M. R.; Rosa, M. D.; Soriente, A.; Scettri, A. Tetrahedron: Asymmetry 2004, 15,
2421–2424.
5. Weibel, E. K.; Hadvary, P.; Hochuli, E.; Kupfer, E.; Lengsfeld, H. J. Antibiot. 1987,
40, 1081–1085.
6. Vogl, E. M.; Gröger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 1570–
1577. and references cited therein.
Acknowledgments
We thank Science and Technology Commission of Shanghai
Municipality for financial support (Grant No. 07dz22005) and Pro-
fessor Stanley M. Roberts for helpful discussions.
7. (a) Hiroaki, S.; Takeyuki, S.; Noriie, I.; Koichi, T.; Tadamasa, D.; Kimio, O.;
Masakatsu, S. J. Am. Chem. Soc. 1993, 115, 10372–10373; (b) Min, S.; Wen, Z.
Adv. Synth. Catal. 2005, 347, 535–540.
References
8. (a) Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155–3212; (b) Brunel,
J. M. Chem. Rev. 2005, 105, 857–898; (c) Ramón, D. J.; Yus, M. Chem. Rev. 2006,
106, 2126–2208.
1. (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994;
(b)Catalysis Asymmetric Synthesis; Ojima, I., Ed., 2nd ed.; Wiley-VCH: New York,
2000; (c)Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. I–III, (d)Lewis Acids in
Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH: New York, 2001.
2. For a review of chiral Lewis acids catalyzed enantioselective aldol reactions of
aldehydes with O-silyldienolates 1 and 2 and the application of enantiomerically
enriched d-hydroxy-b-ketoesters in organic synthesis, see: (a) Soriente, A.; De
Rosa, M.; Villano, R.; Scettri, A. Curr. Org. Chem. 2004, 8, 993–1007; (b) Rosaria, V.;
Maria Rosaria, A.; Antonia, M.; Laura, P.; Scettri, A. Tetrahedron 2009, 65, 5571–
5576; (c) Soriente, A.; Rosa, M. D.; Fruilo, M.; Lepore, L.; Gaeta, C.; Ner, p. Adv.
Synth. Catal. 2005, 347, 816–824; (d) Acocella, M. R.; Rosa, M. D.; Palombi, L.;
Villano, R.; Scettri, A. Tetrahedron 2005, 61, 4091–4097; (e) Villano, R.; Acoc-ela,
M. R.; Rosa, M. D.; Soriente, A.; Scettri, A. Tetrahedron: Asymmetry 2006, 17, 3332–
3334; (f) Villano, R.; Acocella, M. R.; Massa, A.; Palombi, L.; Scettri, A. Tetrahedron
Lett. 2007, 48, 891–895.
9. For the effect of additives on BINOL–Ti(IV) complex catalyzed reactions, see:
(a) Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami, K. Inorg. Chim. Acta
1999, 296, 267–272; (b) Breuning, M.; Corey, E. J. Org. Lett. 2001, 3, 1559–
1562; (c) Zimmer, R.; Peritz, A.; Czerwonka, R.; Schefzig, L.; Reißig, H.-U. Eur.
J. Org. Chem. 2002, 3419–3423; (d) Matsukawa, S.; Mikami, K. Tetrahedron:
Asymmetry 1995, 6, 2571–2574; (e) Lu, G.; Li, X.; Chen, G.; Chan, W. L.; Chan,
A. S. C. Tetrahedron: Asymmetry 2003, 14, 449–452; (f) Kurosu, M.; Lorca, M.
Synlett 2005, 1109; (g) Kitamoto, D.; Imma, H.; Nakai, T. Tetrahedron Lett.
1995, 36, 1861–1864; (h) Sagawa, S.; Abe, H.; Hase, Y.; Inaba, T. J. Org. Chem.
1999, 64, 4962–4965; (i) Komatsu, N.; Hashizume, M.; Sugita, T.; Uemura, S. J.
Org. Chem. 1993, 58, 7624–7626. and references cited therein; (j) Pescitelli, G.;
Bari, L. D.; Salvadori, P. J. Organomet. Chem. 2006, 691, 2311–2318; (k)
Kureshy, R. I.; Singh, S.; Khan, N. H.; Abdi, S. H. R.; Suresh, E.; Jasra, R. V. Eur. J.
Org. Chem. 2006, 1303–1309.
3. For other recent synthetic methods of enantiomerically enriched d-hydroxy-b-
ketoesters, see: Enzymatic reduction of b,d-diketoesters: (a) Wolberg, M.;
Kaluzna, I. A.; Müller, M.; Stewart, J. D. Tetrahedron: Asymmetry 2004, 15, 2825–
10. Xu, Q.; Yu, J.; Hu, W.; Yang, L. Chinese J. Org. Chem., (Y0911241D), in press.